American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be trypanocidal. We initially discovered that 3'-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3'-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure-activity relationship (SAR) was established, and many potent analogues with IC(50) values in the low nanomolar range were identified. Eight additional analogues were trypanocidal in a cell culture assay, and this indicates that aryl thio semicarbazone is a productive scaffold for killing the parasites. Kinetic studies show that these are time-dependent inhibitors. Molecular modeling studies of the enzyme-inhibitor complex have led to a proposed mechanism of interaction as well as insight into the SAR of the thio semicarbazone series. The nonpeptide nature of this series, small size, and extremely low cost of production suggest this is a promising direction for the development of new antitrypanosome chemotherapy.

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Background and AimsBetter understanding of intrinsic control mechanisms of colonic motility will lead to better treatment options for colonic dysmotility. The aim was to investigate neurogenic and myogenic control mechanisms underlying pan-colonic motor patterns.MethodsAnalysis of in vitro video recordings of whole rat colon motility was used to explore motor patterns and their spatiotemporal organizations and to identify mechanisms of neurogenic and myogenic control using pharmacological tools.ResultsStudy of the pan-colonic spatiotemporal organization of motor patterns revealed: fluid-induced or spontaneous rhythmic propulsive long distance contractions (LDCs, 0.4–1.5/min, involving the whole colon), rhythmic propulsive motor complexes (RPMCs) (0.8–2.5/min, dominant in distal colon), ripples (10–14/min, dominant in proximal colon), segmentation and retrograde contractions (0.1–0.8/min, prominent in distal and mid colon). Spontaneous rhythmic LDCs were the dominant pattern, blocked by tetrodotoxin, lidocaine or blockers of cholinergic, nitrergic or serotonergic pathways. Change from propulsion to segmentation and distal retrograde contractions was most prominent after blocking 5-HT3 receptors. In the presence of all neural blockers, bethanechol consistently evoked rhythmic LDC-like propulsive contractions in the same frequency range as the LDCs, indicating the existence of myogenic mechanisms of initiation and propulsion.ConclusionsNeurogenic and myogenic control systems orchestrate distinct and variable motor patterns at different regions of the pan-colon. Cholinergic, nitrergic and serotonergic pathways are essential for rhythmic LDCs to develop. Rhythmic motor patterns in presence of neural blockade indicate the involvement of myogenic control systems and suggest a role for the networks of interstitial cells of Cajal as pacemakers.

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